Solvent effects on the tautomerization, autoxidation and bondexchange reactions of 2-mercaptopyridine derivatives
Masahiro Furutani1)*，Motoya Sakaguchi1)，Kazuhiro Sasa1)
Department of Chemistry and Biology, National Institute of Technology, Fukui College
Geshi-cho, Sabae, Fukui, 916-8507, Japan

Abstract
Tautomerization, autoxidation and bond-exchange reactions of 2-mercaptopyridine derivatives were
investigated in solution, by using several kinds of solvents. A 2-mercaptopyridine derivative having an Nbenzylamide group was dissolved not only in water but also in cyclohexane, although the solubility
toward such solvents was lower than that toward methanol or chloroform. From the UV-Vis spectra, it
was confirmed that thione-type isomer was major in these solvents except for cyclohexane. Autoxidation
reactions were monitored in methanol or methanol-d4, and ca. 36% of 2-mercaptopyridyl groups wereoxidized into disulfide bonds within a month in 1H-NMR spectral measurements. Bond-exchange
reactions between 2,2’-dipyridyl disulfide and a thiol compound were observed more clearly in methanol
than in chloroform, suggesting a solvent effect to dissolution of corresponding disulfide compounds.

Keywords：solvent effect, tautomerization reaction, autoxidation reaction, bond-exchange reaction, 2mercaptopyridine derivative

Received May 31, 2022; accepted July 19, 2022

1) Department of Chemistry and Biology, National Institute of Technology, Fukui College, Geshi-cho, Sabae,
Fukui, 916-8507, Japan*Corresponding author: Masahiro Furutani, E-mail: furutani@fukui-nct.ac.jp

16

1. Introduction
2-Mercaptopyridine and its derivatives are known
as one of chemical compounds which tautomerize
their molecular structures.1,2) These compounds havea mercapto group at the ortho position on a pyridine
ring, and the tautomerization reaction occurs
between its thione-type and thiol-type isomers(Scheme 1(i)). This reaction is reversible, and theequilibrium state is changed by surrounding
conditions of the molecules, such as polarity,3,4)
temperature,5) and concentration.6) For example, it is
known that 2-mercaptopyridines are tautomerized tothe thione-type isomer in the crystal7) and polar
solvents.4) 2-Mercaptopyridines would minimize
their potential energy toward micro-environments
via their tautomerization reaction, and they would
maximize the interaction according to theirenvironments, which would be called as“environmental adaptation”.
Based on this concept, a vinyl monomer having a
2-mercaptopyridyl (2MP) moiety has been designed
andcopolymerizedwith2-hydroxyethyl
methacrylate (HEMA) by using a radical photoinitiator, for photo-adhesion between substrates ofdissimilar materials Poly(HEMA-1), Fig 1).8)
Molecular states of 2MP moieties at the interface
between the photo-adhesive layer and a substratesurface were investigated by X-ray photo-electron
spectroscopic (XPS) measurements, finding that
2MP groups were tautomerized from thione-type tothiol (thiolate)-type isomers at a copper surface due
to sulfur-copper interaction.9) However, systematicinvestigation on the influence of environmental
polarity has not been performed. Furthermore, thephoto-adhesive samples enforced their adhesivestrength week by week, suggesting formation ofcross-linking points through autoxidation of 2MP
moieties to 2,2’-dipyridyl disulfide bonds.8,10)
Autoxidation to disulfides is another unique reactionof 2-mercaptopyridines (Scheme 1(ii)), which is
known to be underwent in water, methanol ordioxane (concentration: 0.02-1 mM).4) However, it isunknown how similar oxidation reactions proceed at

(i)
N
H

S

N

thione-typeSHthiol-type
(ii)

1
2

N

S
2

Scheme 1. (i) Tautomerization reaction between
thione-type and thiol-type isomers of 2mercaptopyridine, and (ii) autoxidation reaction
from its thiol-type isomer to the corresponding
disulfide.

Fig 1. Chemical structures of a photo-adhesivepolymer material containing 2-mercaptopyridyl
moieties (Poly(HEMA-1)), and of the modelcompound 1 using in this study.

a higher concentration. In this article, compound 1
having a 2MP moiety was designed and synthesized
as a model compound of the side chain ofPoly(HEMA-1), and 1 was subjected to polar andnonpolar environments by using water and organic
solvents, to examine the dominant molecular state
among thione-type isomer, thiol-type isomer, anddisulfide for each solvent.
On the other hand, as shown in Scheme 2, it is also
17known that disulfide bonds are exchanged bynitrogen gas, and then dissolved in DCM/THF (7/8,

addition of a thiol compound through a disulfide-v/v). WSCI HCl (0.78g, 5.0 mmol) was added andthiol exchange reaction.11) Polymer materials

stirred at room temperature for 1 h. Benzylamine

containing disulfide bonds are reported to be(0.51 g, 4.8 mmol) and 4-dimethylaminopyridine

decomposed by immersion into solution of low-

(0.49 g, 4.0 mmol) were then added at 0oC, andmolecular-weight thiols.12-14) In this article, effect ofstirred over-night. After evaporating, the residue wassolvent polarity to the bond-exchange reactions wastriturated with ethyl acetate twice, followed byalso examined by using 2,2’-dipyridyl disulfide 2

condensing the extract. Purification was performed

and a thiol, for applying polymer materials

with a silica gel chromatography (eluent: CHCl3 tocontaining

cross-linking

CHCl3/MeOH (100/1, v/v)) to obtain 1 in a 5.4%

moieties15,16) as chemo-degradable materials inyield as a yellow solid. 1H-NMR (400 MHz, CDCl3):

future.

 4.70 (2H, m, -CH2-), 6.91 (1H, m, Py-H), 7.2-7.5

dipyridyl

disulfide(5H, m, Ar-H), 7.66 (1H, m, Py-H), 8.79 (1H, m, Py-

2. Experimental
2.1 Materials and Equipment. 2Mercaptonicotinic acid, benzylamine, 2,2’dipyridyl disulfide 2, [4-(tert-butyl)phenyl]
methanethiol (tBPMT), DL-dithiothreitol (DTT), andcyclohexane were purchased from Tokyo Chemical
Industry Co., Ltd. (Tokyo, Japan). Water soluble
carbodiimide hydrochloride (WSCI HCl) was
purchased from WATANABE CHEMICALINDUSTRIES, Ltd. (Hiroshima, Japan). 4Dimethylaminopyridine,
methanol(MeOH),
chloroform (CHCl3), ethyl acetate, and magnesium
sulfate were purchased from NACALAI TESQUE,
Inc. (Kyoto, Japan). Tetrahydrofuran (THF),
dichloromethane (DCM), and chloroform-d (CDCl3)
were purchased from FUJIFILM Wako Pure
Chemical Corporation (Osaka, Japan). Methanol-d4(CD3OD) was purchased from Sigma-Aldrich Japan(Tokyo, Japan). All chemicals were used without
further purification.
1H- and 13C-NMR spectra were recorded using a
Bruker AVANCE III. APCI-MS spectra wererecorded using an AB Sciex API2000. UV-Vis
spectral measurements were performed using a U0080D (Hitachi High-Tech Science Corporation).

H), 11.1 (1H, br, -CONH-), 12.6 (0.6H, br, -NHCS-).
13C-NMR (125 MHz, CDCl ):  44, 114, 128, 128,3

129, 129, 133, 137, 139, 143, 164. APCI-MS([M+H]+): 245.1 (found), 244.34 (calcd for
C13H12O1N2S1).

e ×104 [ L/(mol・cm) ]

1.5

1.0
Water

MeOH
0.5

CHCl3
Cyclohexane

×30
0.0
300

350

400
450
Wavelength [nm]500

Fig 2. UV-Vis spectra of 1 in water (0.006 mM),
MeOH (0.05 mM), CHCl3 (0.05 mM) andcyclohexane (0.024 mM).

2.3 Tautomerization reactions. Using
compound 1, 0.05 mM (with MeOH or CHCl3),
0.024 mM (with cyclohexane), and 0.006 mM (withwater) of solution samples were prepared, to record
each UV-Vis spectrum at room temperature.
2.4 Autoxidation reactions. Using compound
1, 0.05 mM of solution sample was prepared with
MeOH. These samples were allowed to stand in dark
at room temperature, subjected to interval UV-Vis

2.2 Synthesis. Compound 1 having a 2mercaptopyridyl moiety was synthesized as follows.
2-Mercaptonicotinic acid (0.51 g, 3.3 mmol) was
added to a flask that was dried and purged with18

spectral measurements. Another condense solution

indicating autoxidation of 1 to the disulfide

of 1 (50 mM) was also prepared with CD3OD. This

compound via tautomerization reaction from thesolution was subjected to interval 1H-NMR spectralthione-type to the thiol-type isomers (Fig 3). On themeasurements under the same standing conditions.

other hand, Fig 4 shows 1H-NMR spectral changes

After 79 days, an equivalent of DTT was added andof 1 in CD3OD at a higher concentration (oneallowed to stand in dark at room temperature forthousand times higher than that in UV-Vis spectral

more 38 h, followed by a

1

H-NMR spectral

measurements). Peaks at 8.60, 7.84, and 6.99 ppm

measurement.

were assigned to protons of the 2MP group of thethione-type isomer, while peaks at 8.77, 8.33, and

2.5 Bond-exchange reactions with a thiol.
Using 2, 0.05 mM of solution samples were preparedwith MeOH or CHCl3. tBPMT (10 equiv.) was thenadded to each solution, which was kept at room
temperature or 50oC for interval UV-Vis spectral
measurements.

7.50 ppm were assigned to protons of that of thecorresponding disulfide compound. The latter peaks
were appeared gradually day by day, anddisappeared after adding DTT (a reducing reagent)to the CD3OD solution. It was estimated that ca. 36%
of 1 was oxidized to the corresponding disulfide
after 33 days. It was also observed that the disulfide

3. Results and Discussion
3.1 Tautomerization reactions. Surprisingly,
compound 1 was dissolved into nonpolar solvents aswell as polar solvents. In UV-Vis spectra, the thionetype isomer of 2-mercaptopyridines has a broad peakaround 350-400 nm that is assigned to n-*transition. For compound 1, such peak was observed
clearly in the cases using water, MeOH or CHCl3 as
solvent, except for the case of cyclohexane (Fig 2).
The values of permittivity are 2.02 (cyclohexane),
4.81 (CHCl3), 33.0 (MeOH), and 80.1 (water),17) andthe peak was blue-shifted by increasing permittivity,
or solvent polarity. The molar extinction coefficiente was high in cases of polar solvents, indicating thatthione-type isomer was superior to thiol-type isomer
in a polar environment. Comparing the results
between CHCl3 and MeOH, it was found that both
wavelength of the peak top and the value of e were
almost the same, and that there is a nonlinear
relationship between permittivity and thethione/thiol ratio.

compound was generated just after starting themeasurement (0 day in Fig 4), indicating that 1 wasoxidized easily. In the photo-adhesive polymer
material Poly(HEMA-1), see Fig 1),8) ratio of 2MP
groups toward hydroxy groups from HEMA was 1.3
mol%, and the concentration of 2MP groups in theadhesive layer was calculated to ca. 110 mM.
Although both the concentration and mobility of
2MP groups are still different, similar oxidation

0.3

0d
1
5
11
20
29

Abs.

0.2

0.1

0.0
300

3.2 Autoxidation reactions. A MeOH solutionof 1 was allowed to stand in dark at room
temperature, to measure time course of UV-Vis
spectral changes. The peak intensity at 379 nm wasdecreased gradually with an isosbestic point,

350

400
450
Wavelength [nm]500

Fig 3. UV-Vis spectral changes of 1 in MeOH
(0.05 mM) where the sample was allowed tostand in dark at room temperature.

19

Fig 4. 1H-NMR spectral changes of 1 in CD3OD (50 mM) where the sample was allowed to stand in dark
at room temperature.

reactions to form disulfide bonds (i.e. cross-linking

3.3 Bond-exchange reactions with a thiol.
As shown in Fig 5(a), UV-Vis spectral changes wereobserved, when ten equivalents of a thiol compound(tBPMT) was added to 2,2’-dipyridyl disulfide 2 in
MeOH. A broad peak was appeared immediatelyaround 360 nm, and the peak intensity was saturated
within 4 h. This peak is assigned to n-* transitionof the thione-type isomer of 2-mercaptopyridine,points in the adhesive layer) would proceed. There
are small additional peaks in the region from 8.6 to
7.5 ppm after 17 and 33 days in Fig 4. Although clear
assignment was not achieved, these peaks could be
assigned to protons of 2MP groups of the thiol-type
isomer of 1, or supramolecular complexes wherecompound 1 stacks noncovalently with each othervia hydrogen bonds of two amide bonds.

(b)

(a)

0.2

0.2

0.1

0.05

0.0
300

0.15

5
4
3
2
1
0.5
0h
Before adding

350

400
450
Wavelength [nm]

Abs.

Abs.

0.15

0.1

0.05

0.0
300

500

350

400
450
Wavelength [nm]500

Fig 5. UV-Vis spectral changes of 2 in (a) MeOH (0.05 mM) and (b) CHCl3 (0.05 mM), after adding ten
equivalents of tBPMT where the sample was allowed to stand in dark at room temperature.

20

solvents. Results on the MeOH (or CD3OD)
solution of 1 would be indirect evidences for themolecular behavior of 2MP groups ofPoly(HEMA-1) in the adhesive layer.8,10)
Furthermore, results on the bond-exchange
reactions between 2 and a thiol compound would
give us a hint to fabricate an effective chemodegradable polymer material, because the bondexchange reaction was almost irreversible
theoretically, due to fast tautomerization reactionsof 2-mercaptopyridine to the thione-type isomer.

generated by the disulfide-thiol exchange reactions
shown in Scheme 2. A similar experiment was
performed with CHCl3 as solvent, instead of MeOH.
In this case, however, the corresponding peak did notappear even after 5 h (Fig 5(b)). These results
suggest that the bond-exchange reactions between 2
and tBPMT do not proceed in CHCl3, because thethiol-type isomer tautomerize immediately to thethione-type isomer in CHCl3 as well as in MeOH, if
2-mercaptopyridine is generated by the bondexchange reactions between 2 and tBPMT.
Solubility of 2 toward CHCl3 (or solubility of the

Acknowledgement. MF acknowledges Prof.
Eiki Matsui at National Institute of Technology,
Fukui College for the use of APCI-MS instrument
and UV-Vis spectrometer. This work was supported
by a research grant from Advanced Research Center
for Regional Cooperation, National Institute ofTechnology, Fukui College.

resulting asymmetric disulfide compound toward
MeOH) would be superior to that toward MeOH (orCHCl3), which could disturb the progress of thebond-exchange

reaction.

Time

coursesofabsorbance at the maximum absorption wavelength
in the experiments are shown in Fig. 6. It was also
found that the bond-exchange reactions proceeded alittle even in CHCl3, when the solution was heated at

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